North Carolina macular dystrophy is caused by a novel duplication leading to an upregulation of PRDM13 transcription factor

Abstract

Purpose : To determine the mutation in two families with autosomal dominant North Carolina macular dystrophy (NCMD).

Methods : Microsatellite markers for the MCDR1 locus on chromosome 6q14-q16.2 were used to genotype two large families with NCMD. Then, whole genome next-generation sequencing was performed for 11 members of the two families. The overexpression of CCNC and PRDM13 orthologues were tested specifically in the eye of Drosophila melanogaster.

Results : The same 98.4 kb novel tandem duplication was identified in the two families and confirmed using Sanger sequencing. The duplication contained two entire contiguous genes CCNC and PRDM13, and cosegregated with the disease phenotype. In Drosophila, overexpression of CCNC orthologue had no effect whereas the overexpression of PRDM13 orthologue strongly affected the eye-antennal disc development.

Conclusions : We identified a novel causative mutation, a tandem duplication, in two independent families with NCMD. The duplication encompasses two entire genes, CCNC and PRDM13. Overexpression of PRDM13 but not CCNC in Drosophila leads to an almost complete loss of the imaginal eye-antennal disc, suggesting that the upregulation of the transcription factor PRDM13 is the cause of NCMD.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.